Effects of Antipsychotic Drugs on the Epigenetic Modification of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampi of Chronic Restraint Stress Rats.

Mi Kyoung Seo,Jung Goo Lee,Gyung-Mee Kim,Sung Woo Park,Yena Lee,Roger S Mcintyre,Nicole E Carmona,Rodrigo B Mansur,Young Hoon Kim,Ah Jeong Choi

doi:10.1155/2018/2682037

Abstract

Recent studies have shown that antipsychotic drugs have epigenetic effects. However, the effects of antipsychotic drugs on histone modification remain unclear. Therefore, we investigated the effects of antipsychotic drugs on the epigenetic modification of the BDNF gene in the rat hippocampus. Rats were subjected to chronic restraint stress (6 h/d for 21 d) and then were administered with either olanzapine (2 mg/kg) or haloperidol (1 mg/kg). The levels of histone H3 acetylation and MeCP2 binding at BDNF promoter IV were assessed with chromatin immunoprecipitation assays. The mRNA levels of total BDNF with exon IV, HDAC5, DNMT1, and DNMT3a were assessed with a quantitative RT-PCR procedure. Chronic restraint stress resulted in the downregulation of total and exon IV BDNF mRNA levels and a decrease in histone H3 acetylation and an increase in MeCP2 binding at BDNF promoter IV. Furthermore, there were robust increases in the expression of HDAC5 and DNMTs. Olanzapine administration largely prevented these changes. The administration of haloperidol had no effect. These findings suggest that the antipsychotic drug olanzapine induced histone modification of BDNF gene expression in the hippocampus and that these epigenetic alterations may represent one of the mechanisms underlying the actions of antipsychotic drugs.

Highlights

Schizophrenia is a complex and chronic mental illness with a lifetime prevalence of approximately 1% [1, 2]
A post hoc analysis for the main effect of restraint stress revealed that stress decreased the level of total BDNF mRNA relative to the vehicle control (p = 0 001), while the post hoc analysis for the main effect of treatment revealed that chronic
The present study investigated whether antipsychotic drugs influenced exon IV BDNF mRNA expression in the stress-free and stress conditions (Figure 1(b))

Summary

Introduction

Schizophrenia is a complex and chronic mental illness with a lifetime prevalence of approximately 1% [1, 2]. It is a genetic disorder with a heritability of up to 80% [3], and the majority of patients with schizophrenia suffer from psychotic, affective, and cognitive symptoms as well as functional impairments [4,5,6]. The roles of multiple epigenetic mechanisms in the development of schizophrenia are becoming a primary focus of research [7, 10, 11]. Epigenetic modifications are most commonly regulated by DNA methylation and histone

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